Opioids act on three G protein-coupled receptors (GPCRs) that is, μ (MOR), δ (DOR), and κ (KOR), but it appears that the analgesic action of many commonly used opioid analgesics is mediated primarily via the MOR. It is known that activation of MORs, which are widely expressed in the central nervous system (CNS), peripheral nervous system and peripheral tissues, is responsible not only for beneficial (analgesia) effects but also for a number of several centrally mediated adverse effects, which limits their clinical usefulness. Adverse effects associated with MOR opioid analgesics include respiratory depression, nausea, sedation, dizziness, vomiting, hypotension, and constipation. Long-term use of such opioids can cause tolerance, and thus complicating optimal pain treatment. Another concern with the prolonged use of opioids is physical dependence and development of addictive disorders. On the other hand, the therapeutic utility of the so far known KOR agonists is associated with dose-limiting effects including dysphoria, sedation and other neuropsychiatric adverse effects. Besides the analgesic activity, KOR agonists have also shown other beneficial actions such as anti-pruritic, anti-arthritic, anti-inflammatory, and neuroprotective effects.
As it is the case for other GPCRs, also for MOR, DOR and KOR agents with agonistic effects can be separated from those with antagonistic effects. An agonist is an agent that binds to a receptor and activates that receptor in order to mimic the action of the naturally occurring, endogenous transmitter-molecule. A therapeutically used agonist typically has the same or a stronger affinity to the respective receptor than the endogenous transmitter-molecule. An antagonist, on the other hand, is an agent that binds to a receptor but does not elicit the response that the endogenous transmitter-molecule would trigger. Instead, the antagonist blocks the receptor and prevents its activation by endogenous transmitter-molecules or agonistic drugs.
In the case of opioids, morphine, oxycodone or fentanyl, for example, act as classical agonists. When morphine enters the brain, it binds to opioid receptors and activates them. In case of a morphine overdose, where the high dose of morphine may cause respiratory depression and a drastic drop in blood pressure and heart rate, one may administer naloxone, an opioid antagonist. Naloxone competes with morphine for binding to the receptors, but with a higher affinity than morphine and thus, replaces much of the morphine at the respective receptors. In cases of opioid-addiction, naloxone can allay withdrawal symptoms (nausea, vomiting, hallucinations, tremors, anxiety, etc.). A third class of opioids comprises drugs acting as a partial agonist (or mixed agonists-antagonists) at a single receptor (e.g. buprenorphine) showing an analgesic ceiling effect. A fourth class includes drugs being an agonist or partial agonist at one receptor and an antagonist at another receptor (e.g. the weak MOR-antagonists and partial KOR agonists: pentazocine, butorphanol, nalbuphine). These drugs can be classified as nalorphine-like or morphine-like. And finally there are those, which do not fit into either classification and form a separate class (e.g. meptazinol).
There are three traditional types of pharmacotherapy of opioid addiction (i) antagonists that bind to the opioid receptors with higher affinity than agonists but do not activate the receptor (e.g. naloxone or naltrexone), (ii) agonist treatment (e.g. methadone), and (iii) other agents (e.g. buprenorphine, clonidine) to help withdrawal from opioid drugs as a means of entry into treatment. Some opioid antagonists are not pure antagonists but in fact do produce some weak opioid partial agonist effects, and can produce analgesic effects when administered in high doses to opioid-naive individuals. Examples of such compounds include nalorphine and levallorphan. Some opioids can also have disadvantages such as worsening respiratory depression in patients who have overdosed on non-opioid sedatives such as alcohol or barbiturates.
Opioid antagonists have therapeutic potential in the treatment of a variety of disorders. These include, for instance, constipation, drug addiction, food intake, shock, alcoholism, mental and stress related disorders. The universal opioid antagonist naloxone, which is a competitive antagonist of all three types of opioid receptors (MOR, KOR and DOR), is being used to reverse the potentially lethal respiratory depression caused by neurolept analgesia or opioid overdose.
Among other pharmacological effects, it antagonizes the blood pressure drop in various forms of shock, reverses neonatal hypoxic apnea, counteracts chronic idiopathic constipation, reduces the food intake in humans and shows beneficial effects in central nervous system injuries. Its analogue naltrexone has considerable and longer duration of action higher oral efficacy, which make it suitable for the management of opioid and alcohol dependence. The opioid antagonist nalmefene (Selincro®), an analogue of naltrexone, was launched in Europe in 2013 for the reduction of alcohol consumption in alcohol dependent patients.
Several ligands, both small-molecules and peptides, interacting with the KOR have been developed over the years. The major classes of KOR agonists comprise benzomorphans (e.g. bremazocine, pentazocine), morphinans (e.g. nalfurafine), arylacetamides (e.g. U50,488, 2-(3,4-dichlorophenyl)-N-methyl-N-[(1R,2R)-2-pyrrolidin-1-ylcyclohexyl]acetamide U69,593, N-methyl-2-phenyl-N-[(5R,7S,8S)-7-(pyrrolidin-1-yl)-1-oxaspiro[4.5]dec-8-yl]acetamide), neoclerodane diterpenes (e.g. salvinorin A and analogues), and peptides (e.g. dynorphin analogues). Some notable examples of selective KOP receptor antagonists include the morphinans nor-binaltorphimine (nor-BNI) and 5′-guanidinonaltrindole (GNTI), and the structurally distinct molecule JDTic, a trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine derivative, the latter was used to elucidate the crystal structure of the human KOP receptor. In contrast to the aforementioned KOR antagonists (nor-BNI, GNTI and JDTic) known to exhibit long-lasting pharmacokinetic properties, shorter-acting and selective KOR antagonists were developed, such as the new JDTic analogue BU09059, and the pyrrolidine derivative LY-2456302, the latter one is currently under development as an augmentation to anti-depressant therapy for treatment-resistant depression. In addition to dynorphin A analogues, arodyn (Ac[Phe1,2,3,Arg4,D-Ala8]dynorphin A-(1-11) amide), zyklophin ([N-BenzylTyr1,cyclo(D-Asp5,Dap8)]dynorphin A(1-11)-NH2), and other peptides unrelated to the endogenous opioid peptide were recognized as selective KOR antagonists, for example the macrocyclic peptide cyclo[Phe-D-Pro-Phe-Trp] (CJ-15,208) and derivatives.
In the Journal of Medicinal Chemistry 2012, 55, pp. 10302-10306, six 3-hydroxy substituted diphenethylamine derivatives bearing different substituents at the nitrogen were described as KOR ligands. The N-cyclobutylmethyl substituted derivative (compound 4 in Journal of Medicinal Chemistry 2012, 55, pp. 10302-10306, referred to herein as HS665) was found to have the highest antinociceptive potency of this series.